Decrease In Lesion Size Research Articles

Single-cell analysis identifies distinct macrophage phenotypes associated with prodisease and proresolving functions in the endometriotic niche

Endometriosis negatively impacts the health-related quality of life of 190 million women worldwide. Novel advances in nonhormonal treatments for this debilitating condition are desperately needed. Macrophages play a vital role in the pathophysiology of endometriosis and represent a promising therapeutic target. In the current study, we revealed the full transcriptomic complexity of endometriosis-associated macrophage subpopulations using single-cell analyses in a preclinical mouse model of experimental endometriosis. We have identified two key lesion-resident populations that resemble i) tumor-associated macrophages (characterized by expression of Folr2, Mrc1, Gas6, and Ccl8+) that promoted expression of Col1a1 and Tgfb1 in human endometrial stromal cells and increased angiogenic meshes in human umbilical vein endothelial cells, and ii) scar-associated macrophages (Mmp12, Cd9, Spp1, Trem2+) that exhibited a phenotype associated with fibrosis and matrix remodeling. We also described a population of proresolving large peritoneal macrophages that align with a lipid-associated macrophage phenotype (Apoe, Saa3, Pid1) concomitant with altered lipid metabolism and cholesterol efflux. Gain of function experiments using an Apoe mimetic resulted in decreased lesion size and fibrosis, and modification of peritoneal macrophage populations in the preclinical model. Using cross-species analysis of mouse and human single-cell datasets, we determined the concordance of peritoneal and lesion-resident macrophage subpopulations, identifying key similarities and differences in transcriptomic phenotypes. Ultimately, we envisage that these findings will inform the design and use of specific macrophage-targeted therapies and open broad avenues for the treatment of endometriosis.

Hepatocyte Growth Factor Delivery to Injured Cervical Spinal Cord Using an Engineered Biomaterial Protects Respiratory Neural Circuitry and Preserves Functional Diaphragm Innervation.

A major portion of spinal cord injury (SCI) cases occur in the cervical region, where essential components of the respiratory neural circuitry are located. Phrenic motor neurons (PhMNs) housed at cervical spinal cord level C3-C5 directly innervate the diaphragm, and SCI-induced damage to these cells severely impairs respiratory function. In this study, we tested a biomaterial-based approach aimed at preserving this critical phrenic motor circuitry after cervical SCI by locally delivering hepatocyte growth factor (HGF). HGF is a potent mitogen that promotes survival, proliferation, migration, repair, and regeneration of a number of different cell and tissue types in response to injury. We developed a hydrogel-based HGF delivery system that can be injected into the intrathecal space for local delivery of high levels of HGF without damaging the spinal cord. Implantation of HGF hydrogel after unilateral C5 contusion-type SCI in rats preserved diaphragm function, as assessed by invivo recordings of both compound muscle action potentials and inspiratory electromyography amplitudes. HGF hydrogel also preserved PhMN innervation of the diaphragm, as assessed by both retrograde PhMN tracing and detailed neuromuscular junction morphological analysis. Furthermore, HGF hydrogel significantly decreased lesion size and degeneration of cervical motor neuron cell bodies, as well as reduced levels surrounding the injury site of scar-associated chondroitin sulfate proteoglycan molecules that limit axon growth capacity. Our findings demonstrate that local biomaterial-based delivery of HGF hydrogel to injured cervical spinal cord is an effective strategy for preserving respiratory circuitry and diaphragm function.

Epidemiological observations and management challenges in extrapedal mycetoma: A three-decade review of 420 cases.

Mycetoma is a serious, destructive, disfiguring chronic granulomatous inflammatory disease affecting the subcutaneous tissues that spread to involve the skin, deep tissues and bone. The disease predominately affects the limbs, and extrapedal mycetoma is rarely reported. The reported extrapedal ones are characterised by high morbidity and mortality. This communication reports on 420 patients with extrapedal mycetoma seen and managed at the Mycetoma Research Centre (MRC), University of Khartoum, between January 1991 and December 2021. In this descriptive, cross-sectional, hospital-based study, the electronic records of all mycetoma-confirmed patients seen during the study period were carefully and meticulously reviewed. The confirmed patients with extrapedal mycetoma were included in this study. The study included 420 patients with extrapedal mycetoma, 298 (70.7%) had eumycetoma, and 122 (29.3%) had actinomycetoma. There were 343 male patients (81.7%) and 77 (18.3%) females, with a male-to-female ratio of 4:1. Their ages ranged between 1.5 and 95 years, with a median of 28 years. Most of the patients were students and farmers. The majority of patients were from El Gezira, North Kordofan, and the White Nile States. Mycetoma was painful in 21%, and a family history of mycetoma was recorded in 11.5% of patients. The buttocks (37.9%) and head and neck (16.9%) were affected most. Less frequently affected sites were the trunk and back (12%) each, abdominal and chest walls (4.5%) each and loin (1%). The prominent clinical presentation findings were multiple sinuses discharging grains (55%), massive swellings (46%), and lymphadenopathy (11.5%). Less commonly observed clinical findings were local hyperhidrosis (5.3%) and dilated tortuous veins close to mycetoma lesions (0.5%). The study showed that 204 patients (48.6%) had clinical improvement in terms of decreased lesion size and healing of sinuses following medical therapy. Sixty-six patients (15.7%) had no noticeable improvement. The lesion continued progressing despite treatment in 44 patients (10.5%). In the study, 118 patients were on regular follow-up, and in this group, a cure was documented in 25 patients (21.1%) with eumycetoma and 23 (19.4%) with actinomycetoma. Post-operative recurrence among eumycetoma patients was 40%, with a 1% mortality rate. The treatment outcome was unsatisfactory, characterised by a low cure rate, high recurrence (40%) and follow-up dropout (57%) rates. This emphasises the importance of early case detection and management, objective health education programmes and thorough patient counselling to urge people to seek treatment early and reduce dropouts.

The WY Domain of an RxLr Effector Drives Interactions with a Host Target Phosphatase to Mimic Host Regulatory Proteins and Promote Phytophthora infestans Infection.

Plant pathogens manipulate the cellular environment of the host to facilitate infection and colonization that often lead to plant diseases. To accomplish this, many specialized pathogens secrete virulence proteins called effectors into the host cell, which subvert processes such as immune signaling, gene transcription, and host metabolism. Phytophthora infestans, the causative agent of potato late blight, employs an expanded repertoire of RxLR effectors with WY domains to manipulate the host through direct interaction with protein targets. However, our understanding of the molecular mechanisms underlying the interactions between WY effectors and their host targets remains limited. In this study, we performed a structural and biophysical characterization of the P. infestans WY effector Pi04314 in complex with the potato Protein Phosphatase 1-c (PP1c). We elucidate how Pi04314 uses a WY domain and a specialized C-terminal loop carrying a KVxF motif that interact with conserved surfaces on PP1c, known to be used by host regulatory proteins for guiding function. Through biophysical and in planta analyses, we demonstrate that Pi04314 WY or KVxF mutants lose their ability to bind PP1c. The loss of PP1c binding correlates with changes in PP1c nucleolar localization and a decrease in lesion size in plant infection assays. This study provides insights into the manipulation of plant hosts by pathogens, revealing how effectors exploit key regulatory interfaces in host proteins to modify their function and facilitate disease. [Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY 4.0 International license.

Reproducible Quantitative Trait Loci for Resistance to Soft Rot Caused by Dickeya dianthicola Derived from the Wild Potato Solanum microdontum (PI 458355) Are Located on Chromosomes 1, 3, and 5.

The potato wild relative Solanum microdontum is a breeder-friendly source of genetic resistance to soft rot. Our objectives were to (i) identify loci associated with soft rot resistance in S. microdontum germplasm and (ii) develop bi-parental populations in a self-compatible S. tuberosum genetic background to recover segregating F2 progenies, construct a linkage map, and identify quantitative trait loci (QTLs). Under objective (i), tubers from 103 S. microdontum genotypes from the United States Potato Genebank were inoculated with a high virulence strain of Dickeya dianthicola, and lesion size was measured after a 24-h incubation period at 30°C. Association analysis using 3,490 polymorphic Infinium array SNP markers identified soft rot resistance loci on chromosomes 1, 2, 3, 5, 7, 8, 11, and 12. Under objective (ii), a resistant S. microdontum accession PI 458355 was crossed with a highly fertile, self-compatible, diploid S. tuberosum pollen parent (PI 654351) to generate segregating F2 populations. Composite interval mapping was conducted using a genetic linkage map with 970 GBS-based SNP markers. Reproducible QTLs were detected on chromosomes 1, 3, and 5, explaining 11, 13, and 23% of the phenotypic variation, respectively. Homozygous S. microdontum alleles at the QTL on chromosome 5 and heterozygous or homozygous S. microdontum alleles at QTLs on chromosomes 1 and 3 significantly decrease lesion size compared with the homozygous S. tuberosum parent. The germplasm created in these studies provides a resource for studying traits from S. microdontum, and we can use the advanced F2 selections for future potato improvement. [Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Effect of lactobacillus reuteri-derived probiotic nano-formulation on recurrent aphthous stomatitis: a double-blinded randomized clinical trial

ObjectivesWe aimed to assess the therapeutic effects of a topical probiotic nano-formulation derived from Lactobacillus reuteri on treating recurrent aphthous stomatitis.Materials and methods60 participants were randomly allocated into two groups (control and probiotic). Probiotic group administered topical probiotic nano-formulation three times a day for seven days. The control group administered a standard analgesic oral rinse. The size of ulcer(s) and pain severity were recorded on days 0, 3, 5, and 7 after intervention.ResultsBefore the intervention, the groups had no significant differences in terms of pain severity (P-value = 0.28) and lesion size (P-value = 0.24). Both groups exhibited significant reductions in pain severity and lesion size over the course of the intervention. After one week, the probiotic group had a notably larger lesion size reduction than the control group (P-value = 0.01). The probiotic group also showed a significantly greater reduction in pain severity than the control group (P-value = 0.04).ConclusionsApplying topical probiotic nano-formulation derived from Lactobacillus reuteri three times a day decreased lesion size and pain severity in RAS patients faster than the local analgesic oral rinse.Clinical relevanceLactobacillus reuteri-derived probiotic nano-formulation might be a promising treatment option for RAS.

Supracerebellar infratentorial resection of a torcular lesion causing fulminant intracranial hypertension: illustrative case.

Venous sinus stenosis has been implicated in intracranial hypertension and can lead to papilledema and blindness. The authors report the unique case of a cerebellar transtentorial lesion resulting in venous sinus stenosis in the torcula and bilateral transverse sinuses that underwent resection. A 5-year-old male presented with subacute vision loss and bilateral papilledema. Imaging demonstrated a lesion causing mass effect on the torcula/transverse sinuses and findings of increased intracranial pressure (ICP). A lumbar puncture confirmed elevated pressure, and the patient underwent bilateral optic nerve sheath fenestration. Cerebral angiography and venous manometry showed elevated venous sinus pressures suggestive of venous hypertension. The patient underwent a craniotomy and supracerebellar/infratentorial approach. A stalk emanating from the cerebellum through the tentorium was identified and divided. Postoperative magnetic resonance imaging showed decreased lesion size and improved sinus patency. Papilledema resolved and other findings of elevated ICP improved. Pathology was consistent with atrophic cerebellar cortex. Serial imaging over 6 months demonstrated progressive decrease in the lesion with concurrent improvements in sinus patency. Although uncommon, symptoms of intracranial hypertension in patients with venous sinus lesions should prompt additional workup ranging from dedicated venous imaging to assessments of ICP and venous manometry.

Efficacy and Safety of Makabuhay (Tinospora rumphii) 25% Cream Versus Hydrocortisone 1% Cream in the Management of Mosquito Bite Reactions: Randomized Double-Blind Controlled Trial.

Most insect bite reactions resolve spontaneously, but the inflammation and pruritus induced have been shown to decrease the quality of life. Previous studies have shown the potential anti-inflammatory properties of Tinospora rumphii. The aim of the study is to assess the efficacy and safety of T rumphii 25% cream versus hydrocortisone 1% cream in the management of local cutaneous reactions caused by mosquito bites. This study was a parallel-group, double-blind, randomized, placebo-controlled trial with a 1-week duration in a span of 3 months (June 2019 to August 2019). Participants were exposed to sterile noninfectious mosquitoes (Aedes aegypti) for 5-10 minutes to elicit cutaneous lesions. Tinospora 25% cream or hydrocortisone 1% cream was applied twice daily throughout the 7-day study period. Of the 70 participants screened for this study, which was approved by an institutional review board (IRB 2019-07) at the Dermatology Outpatient Department of the Research Institute for Tropical Medicine, Alabang, Muntinlupa, Philippines, 58 participants in total met the inclusion criteria and were randomized to treatment (Tinospora: n=29) and active control (hydrocortisone: n=29) groups. In total, 58 participants were randomized to receive Tinospora cream (n=29) or hydrocortisone cream (n=29). All participants completed the follow-up. There was a significant decrease in lesion size in both groups from the first 15 minutes to day 7 (P<.001). Comparing the lesion size in both groups, there was a statistically significant decrease in lesion size in the first hour (P=.003) and after 24 hours (P=.03). On day 1, 10% (n=29) of participants in the hydrocortisone group and 7% (n=29) in the Tinospora group experienced complete resolution. On day 3, all participants experienced complete resolution. No adverse effects were documented. Tinospora 25% cream is safe, effective, and comparable to hydrocortisone 1% cream as an anti-inflammatory agent for mosquito bite reactions based on the decrease in lesion size, the proportion of participants with complete resolution of wheals, and improvement in pruritus intensity score using a visual analog scale. Long-term safety studies are recommended. Philippine Health Research Registry PHRR230716-005932; https://www.herdin.ph/index.php/registry?view=research&layout=details&cid=5932.

A Phase 1a/b Trial of Luxeptinib (CG-806) in Patients with Relapsed/Refractory B-Cell Malignancies or Acute Myeloid Leukemia and Evaluation of New G3 Formulation

INTRODUCTION: Luxeptinib (CG-806; LUX) is an orally active noncovalent kinase inhibitor of Bruton's tyrosine kinase (BTK), wild type and mutant forms of Fms-like tyrosine kinase 3 (FLT3) (including the internal tandem duplicates (ITD), tyrosine kinase domain (TKD), and F691L mutant forms), and growth receptors like KIT, CSF1R, PDGFRα, and TRKs. In prior studies, LUX has been shown to suppress aberrant proliferative signaling in B cell malignancies and acute myeloid leukemia (AML) via regulation of BTK, LYN, SYK, AKT, ERK, and MAPK. LUX is cytotoxic to primary AML cells insensitive to other FLT3 inhibitors and to malignant B-cells insensitive to ibrutinib, at pM and nM concentrations, respectively. AIMS: The primary objectives of these studies are to assess the safety, tolerability, and pharmacokinetics (PK) of LUX and determine recommended phase 2 doses for relapsed or refractory (R/R) AML and B cell malignancy patients. METHODS: In two studies (NCT04477291; NCT03893682), LUX (original formulation, G1) was administered continuously as oral capsules BID in 28-day cycles of ascending cohorts (relapsed or refractory de novo, secondary, or therapy-related AML or higher risk myelodysplastic syndrome (MDS), and relapsed and refractory for B cell lymphoma and chronic lymphocytic/small lymphocytic leukemia). A novel generation 3 (G3) formulation of LUX designed to increase bioavailability was tested at a single-dose (sub-study) for relative bioavailability (RBA), followed by continuous dosing in subsequent R/R AML patients. RESULTS: In the B-cell study (as of 15 th May 2023), LUX has been administered to 36 patients at dose levels from 150 mg to 900 mg BID in patients with a median of 3 lines of prior treatment, with 47.2% having received a BTK-inhibitor. Only one (2.8%) patient had a DLT of hypertension and 14 (38.9%) experienced at least one drug related ≥Grade3 treatment emergent adverse event (TEAE). Two patients (900 mg) are currently on study with no DLT and no ≥Grade 3 related TEAEs. A Follicular lymphoma patient is at cycle 28, and achieved a best response as partial response (PR) with a decrease in lesion size of 76.2%; an SLL patient is at cycle 13, and achieved stable disease (SD) showing a decrease in lesion size of 43.1% (Figure A). The overall best response achieved among the 17 patients who have been on treatment for more than 12 weeks are stable disease (SD) (n=11), partial response (PR) (n=3), minor response (n=2) and complete response (CR) (n=1). As of 5 th June 2023, in the AML trial, a total of 40 patients (16 (40%) FLT3-ITD, 21 (52.5%) FLT3-WT, 2 (5.0%) FLT3-TKD, and 1 (2.5%) unknown mutations) with a median of 3 prior treatments (range, 1 - 10) have been treated with LUX G1 formulation at dose levels from 450 mg - 900 mg BID (n=34) or with 50 mg BID of G3 formulation (n=6). Four (10%) experienced drug related SAE and 7 (17.5%) had a drug related grade ≥3 TEAEs. The most common related TEAEs were lymphocyte count decrease, platelet count decrease, and anemia (n=2; 5% patients each). One (2.5%) patient at 450 mg dose, reported complete remission without minimum residual disease (CRmrd) and remained on study for 56 weeks. In the RBA sub-study, G3 (50 mg) produced comparable exposures to G1 (450-900 mg range) (Figure B) and was, therefore, selected as the starting dose for use in the R/R AML study. Six patients were treated with a continuous dosing of 50 mg BID G3; with plasma levels of 274 ng/mL and 195 ng/mL LUX observed by the end of C1D15 and C1D22 respectively. No drug related Grade ≥3 TEAEs or DLTs were observed in 50 mg BID G3 LUX treated patients; with no new safety signals observed for the G3 formulation. Based on these findings and expected exposures for higher dose levels, the cohort safety review committee has approved escalation of G3 dosing to 200 mg BID at which dosing is ongoing. CONCLUSIONS: LUX has a favorable safety profile in patients at all tested dose levels, for multiple cycles, for both studies. Antitumor activity was observed in a heavily pretreated relapsed AML patient and in multiple B-NHL subtypes and CLL/SLL patients including several with prior ibrutinib exposure. Continuous dosing of patients with R/R AML and Higher-Risk MDS with the G3 formulation is ongoing; with updated clinical data (200 mg dose level) to be presented at the meeting.

P‐aminobenzoic acid and vitamin B9 enhance rice defence against sheath blight disease caused by Rhizoctonia solani

AbstractSheath blight is one of the most important rice diseases and its control is generally achieved by the use of fungicides, but the economic and environmental costs involved have led to a search for alternative management approaches. In this study, we evaluated the efficacy of eight defence inducers against the rice sheath blight pathogen, Rhizoctonia solani AG1‐IA. The results showed that 10 mM p‐aminobenzoic acid (PABA) and 3 mM vitamin B9 (VB9)‐treated plants had significantly lower disease indices, at 2.56 and 3.49, respectively, compared to the control at 5.36 in growth room conditions. The direct effect studies showed that PABA significantly suppressed fungal mycelial growth, sclerotial formation and hyphal regeneration ability. However, VB9 showed no effect on mycelial growth but promoted sclerotial formation and hyphal regeneration. Histological observation showed a decreased lesion size and lower amount of hyphal DNA in inducer‐treated leaves. Reverse transcription‐quantitative PCR revealed that OsPR1b was significantly induced by VB9 and the expression of OsPR5 was potentiated by PABA, which indicates that the salicylic acid pathway is possibly involved in VB9‐induced resistance, and the antifungal protein OsPR5 probably contributes partially to PABA protection against R. solani. Immediate control effects of PABA and VB9 were also found after disease establishment. Under greenhouse conditions, the control effects of PABA and VB9 were 29.8% and 40.5%, respectively. These findings reveal that the application of PABA and VB9 to complement plant resistance to sheath blight appears to be an effective strategy.

Extranodal involvement of posttransplant lymphoproliferative disorder detected on 18F‐fluorodeoxyglucose‐positron emission tomography/computed tomography

A 69-year-old man with a history of kidney transplantation presented with ring-enhancing lesions in the left frontal lobe, thalamus, and right insula (Figure 1a) on magnetic resonance imaging. He was hospitalized with a diagnosis of cytomegalovirus encephalitis and had taken anti-inflammatory therapy. Follow up imaging showed a decrease in lesion size in the left frontal lobe and thalamus; however, the right insular lesion increased in size and new ones were identified in the corpus callosum and periventricular white matter (Figure 1a). The tumor markers CA125, CYFRA21-1, CEA, PSA, and fPSA were all positive on blood testing. Because anti-inflammatory therapy was ineffective and malignant tumor could not be excluded on imaging alone, whole-body 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) was performed (Figure 1b). Body imaging showed multiple hypermetabolic nodular lesions in the thoracic and abdominal superficial soft tissue (maximum standardized uptake value, 13.06), which suggested malignancy. Head imaging showed decreased activity in the brain lesions. A diagnosis of lymphoma was suspected. Punch biopsy of a superficial soft tissue nodule was consistent with B cell-derived posttransplant lymphoproliferative disorder (PTLD) (Figure 1c,d). Brain MRI, 18F-FDG PET, and histopathological findings in a 69-year-old male patient with posttransplant lymphoproliferative disorder. (a) Abnormal signals in T2-flair MRI images within 3 months (solid arrow). (b) 18F-FDG PET/CT images show multiple lesions in superficial soft tissue nodules with hypermetabolism and decreased FDG activity of intracranial lesions (solid arrow). (c) Immunohistochemical staining shows positive CD3. (d) Immunohistochemical staining shows enlarged B cells (solid arrow). 18F-FDG, 18F-fluorodeoxyglucose; CT, computed tomography; PET, positron emission tomography. PTLD is a rare group of heterogeneous lymphoproliferative conditions that occur after solid organ or hematopoietic transplantation [1, 2]. With allograft transplantation, the anatomic site of PTLD involvement usually depends on the type of transplant [3]. Reported incidence rates of involvement of the central nervous system range between 10% and 15% [4, 5]. However, simultaneous involvement of the central nervous system [6] and superficial soft tissue [7] are rare. To date, only two cases of PTLD soft tissue nodules have been reported [4]. Characteristics of PTLD on magnetic resonance imaging are not specific; however, PTLD can be detected on 18F-FDG-PET with an overall sensitivity and specificity of approximately 90% [8, 9]. PTLD should be considered when multiple hypermetabolic superficial soft tissue nodules and central nervous system lesions are encountered in transplantation patients. Whole-body18F-FDG-PET/CT is more effective than single-site imaging for diagnosing or staging PTLD. Bojun Wang: Data curation (lead); Writing – original draft (lead). Tianbin Song: Conceptualization (equal); Writing – review & editing (equal). Chun Zhang: Conceptualization (equal); Supervision (equal). Jie Lu: Supervision (equal). Zhigang Liang: Supervision (equal); Writing – review & editing (equal). We thank Dr. Lianghong Teng (Department of Pathology, Xuanwu Hospital, Capital Medical University, Beijing, China) who provided support of pathological picture of this case. All the authors declare that they have no conflict or potential conflict of interest. This article does not contain any studies with animals performed by any of the authors. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the principles of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from the patient and his parents for the anonymous use of his clinical, imaging, and histologic data for publication. The data that support the findings of this study are available from the corresponding author, upon reasonable request.

Antibody blockade of Jagged1 attenuates choroidal neovascularization

Antibody-based blocking of vascular endothelial growth factor (VEGF) reduces choroidal neovascularization (CNV) and retinal edema, rescuing vision in patients with neovascular age-related macular degeneration (nAMD). However, poor response and resistance to anti-VEGF treatment occurs. We report that targeting the Notch ligand Jagged1 by a monoclonal antibody reduces neovascular lesion size, number of activated phagocytes and inflammatory markers and vascular leakage in an experimental CNV mouse model. Additionally, we demonstrate that Jagged1 is expressed in mouse and human eyes, and that Jagged1 expression is independent of VEGF signaling in human endothelial cells. When anti-Jagged1 was combined with anti-VEGF in mice, the decrease in lesion size exceeded that of either antibody alone. The therapeutic effect was solely dependent on blocking, as engineering antibodies to abolish effector functions did not impair the therapeutic effect. Targeting of Jagged1 alone or in combination with anti-VEGF may thus be an attractive strategy to attenuate CNV-bearing diseases.

Association between neurofilament light chain concentration and lesion size in dogs with meningoencephalitis of unknown origin.

Neurofilament light chain (NfL) is an axonal cytoplasmic protein in neurons. Recently, NfL has shown potential as a diagnostic biomarker in dogs with meningoencephalitis of unknown origin (MUO). However, there have been no studies on the biomarkers of lesion progression and resolution in MUO. To identify the potential of NfL as a biomarker for predicting changes in lesions. Seven dogs with MUO who had undergone two magnetic resonance imaging (MRI) scans were included. The serum NfL levels were measured using a single-molecule array. The relationship between the rate of change in lesion size and the rate of change in serum NfL level was analysed using simple linear regression. To investigate the effect of changes in lesion size on NfL levels, the dogs were divided into two groups depending on the change in lesion size: decreased lesion size group (n = 5) and increased lesion size group (n = 2). Trends in lesion size change were identified in the second MRI compared with the first MRI. A significant positive relationship between the rate of lesion size change and the rate of NfL level change was identified (R2 = 0.9239, p = 0.0006). In the decreased lesion size group (n = 5), all NfL levels in each dog decreased, and in the increased lesion size group (n = 2), all NfL levels in each dog increased. This preliminary study showed a positive relationship between the rate of change in lesion size and rate of change in serum NfL levels. Therefore, the serum NfL level may be a promising biomarker of lesion progression and resolution in MUO.

Fingolimod (FTY720) Hinders Interferon-γ-Mediated Fibrotic Scar Formation and Facilitates Neurological Recovery After Spinal Cord Injury.

Following spinal cord injury (SCI), fibrotic scar inhibits axon regeneration and impairs neurological function recovery. It has been reported that T cell-derived interferon (IFN)-γ plays a pivotal role in promoting fibrotic scarring in neurodegenerative disease. However, the role of IFN-γ in fibrotic scar formation after SCI has not been declared. In this study, a spinal cord crush injury mouse was established. Western blot and immunofluorescence showed that IFN-γ was surrounded by fibroblasts at 3, 7, 14, and 28 days post-injury. Moreover, IFN-γ is mainly secreted by T cells after SCI. Further, in situ injection of IFN-γ into the normal spinal cord resulted in fibrotic scar formation and inflammation response at 7 days post-injection. After SCI, the intraperitoneal injection of fingolimod (FTY720), a sphingosine-1-phosphate receptor 1 (S1PR1) modulator and W146, an S1PR1 antagonist, significantly reduced T cell infiltration, attenuating fibrotic scarring via inhibiting IFN-γ/IFN-γR pathway, while in situ injection of IFN-γ diminished the effect of FTY720 on reducing fibrotic scarring. FTY720 treatment inhibited inflammation, decreased lesion size, and promoted neuroprotection and neurological recovery after SCI. These findings demonstrate that the inhibition of T cell-derived IFN-γ by FTY720 suppressed fibrotic scarring and contributed to neurological recovery after SCI.

Colchicine exerts anti-atherosclerotic and -plaque-stabilizing effects targeting foam cell formation.

Colchicine is a broad-acting anti-inflammatory agent that has attracted interest for repurposing in atherosclerotic cardiovascular disease. Here, we studied its ability at a human equivalent dose of 0.5mg/day to modify plaque formation and composition in murine atherosclerosis and investigated its actions on macrophage responses to atherogenic stimuli in vitro. In atherosclerosis induced by high-cholesterol diet, Apoe-/- mice treated with colchicine had 50% reduction in aortic oil Red O+ plaque area compared to saline control (p=.001) and lower oil Red O+ staining of aortic sinus lesions (p=.03). In vitro, addition of 10nM colchicine inhibited foam cell formation from murine and human macrophages after treatment with oxidized LDL (ox-LDL). Mechanistically, colchicine downregulated glycosylation and surface expression of the ox-LDL uptake receptor, CD36, and reduced CD36+ staining in aortic sinus plaques. It also decreased macrophage uptake of cholesterol crystals, resulting in lower intracellular lysosomal activity, inhibition of the NLRP3 inflammasome, and reduced secretion of IL-1β and IL-18. Colchicine's anti-atherosclerotic actions were accentuated in a mouse model of unstable plaque induced by carotid artery tandem stenosis surgery, where it decreased lesion size by 48% (p=.01), reduced lipid (p=.006) and necrotic core area (p=.007), increased collagen content and cap-to-necrotic core ratio (p=.05), and attenuated plaque neutrophil extracellular traps (p < .001). At low dose, colchicine's effects were not accompanied by the evidence of microtubule depolymerization. Together, these results show that colchicine exerts anti-atherosclerotic and plaque-stabilizing effects at low dose by inhibiting foam cell formation and cholesterol crystal-induced inflammation. This provides a new framework to support its repurposing for atherosclerotic cardiovascular disease.

Is dienogest a convenient treatment option for cesarean scar endometriosis or should it be treated surgically?

ObjectivesEndometriosis-related conditions such as subcutaneous endometriosis have been frequently seen in recent years, and dienogest or surgical excision is generally preferred as a treatment option. Our aim in this study is to determine which treatment option will be more effective in reducing the symptoms of patients with cesarean scar endometriosis.Study designThis prospective study was performed with 21 patients diagnosed with cesarean scar endometriosis. The demographic features of the patients, lesion sizes before and after medical and surgical treatment, VAS scores and Ca-125 levels were recorded. VAS scores and lesion sizes were compared before-after medical treatment and before-after surgery in same group. ResultsA total of 18 women were identified, with a mean age of 32.3 ± 5.7 years. No significant decrease in lesion size was observed in the 1st and 6th-month controls after the use of dienogest (p > 0,05), while a significant decrease in VAS scores was detected (p < 0,05). After surgery, the decrease in both lesion size and VAS scores was found statistically significant (p < 0,05). ConclusionDienogest, which is frequently used in the medical treatment of pelvic and ovarian endometriosis, reduces pain minimally in cesarean scar endometriosis but does not provide a change in lesion size. Therefore, surgical treatment of cesarean scar endometriosis seems to be more effective in reducing pain and decreasing the size of the lesions.

Antileishmanial Activity of Clinanthus milagroanthus S. Leiva & Meerow (Amaryllidaceae) Collected in Peru.

Leishmaniasis is a worldwide infectious parasitic disease caused by different species of protozoa of the genus Leishmania, which are transmitted to animals and humans through the bite of insects of the Psychodidae family. In the present work, the antileishmanial activity of an alkaloid extract of the bulbs of Clinanthus milagroanthus S. Leiva & Meerow (Amaryllidaceae) was evaluated in vitro, in vivo, and in silico against the parasite Leishmania braziliensis, and the chemical profile of the sample was determined by GC-MS analysis. At concentrations of 1, 10, and 100 µg·mL−1, the alkaloid extract presented inhibition percentages of 8.7%, 23.1%, and 98.8%, respectively, against L. braziliensis with a p < 0.05, and IC50 values of 18.5 ± 0.3 µg·mL−1. Furthermore, at a dose of 1.0 mg·kg−1, a greater decrease in lesion size was observed (90%) for in vivo assays, as well as a decrease in infection (96%), finding no significant differences (p > 0.05) in comparison with amphotericin B (92% and 98%, respectively). Eleven alkaloids were identified in C. milagroanthus bulbs: galanthamine, vittatine/crinine, 8-O-demethylmaritidine, anhydrolycorine, 11,12-dehydroanhydrolycorine, hippamine, lycorine, 2-hydroxyanhydrolycorine, 7-hydroxyclivonine, 2α-hydroxyhomolycorine, and 7-hydroxyclivonine isomer. A molecular model of Leishmania braziliensis trypanothione reductase (TRLb) was built using computational experiments to evaluate in silico the potential of the Amaryllidaceae alkaloid identified in C. milagroanthus toward this enzyme. The structures galanthamine, 7-hydroxyclivonine isomer, and crinine showed better estimated free energy of binding than the reference compound, amphotericin B. In conclusion, this is the first in vitro, in vivo, and in silico report about the antileishmanial potential and alkaloid profiling of the extract of C. milagroanthus bulbs, which could become an interesting source of bioactive molecules.

Nanoparticle and Stem Cell Combination Therapy for the Management of Stroke.

Stroke is currently one of the primary causes of morbidity and mortality worldwide. Unfortunately, the available treatments for stroke are still extremely limited. Indeed, stem cell (SC) therapy is a new option for the treatment of stroke that could significantly expand the therapeutic time window of stroke. Some proposed mechanisms for stroke-based SC therapy are the incorporation of SCs into the host brain to replace dead or damaged cells/tissues. Moreover, acute cell delivery can inhibit apoptosis and decrease lesion size, providing immunomudolatory and neuroprotection effects. However, several major SC problems related to SCs such as homing, viability, uncontrolled differentiation, and possible immune response, have limited SC therapy. A combination of SC therapy with nanoparticles (NPs) can be a solution to address these challenges. NPs have received considerable attention in regulating and controlling the behavior of SCs because of their unique physicochemical properties. By reviewing the pathophysiology of stroke and the therapeutic benefits of SCs and NPs, we hypothesize that combined therapy will offer a promising future in the field of stroke management. In this work, we discuss recent literature in SC research combined with NP-based strategies that may have a synergistic outcome after stroke incidence.

Outcomes of Intraplaque Verapamil Injection for Treatment of Peyronie’s Disease

Objective: To determine the outcomes of intraplaque verapamil injection for treatment of Peyronie's disease. Aim:The purpose of this study is to evaluate the outcomes &amp; efficacy of intraplaque verapamil injection in Peyronie’s disease management. Methods: The quasi experimental study was conducted from July 2018 to July 2019 on a group of 26 subjects suffering from Peyronie's disease. After detailed history, complete physical and genital examination, the diagnosis was confirmed. After informed consent, questionnaires regarding pain and sexual satisfaction of patients were filled. All patients received verapamil injections on weekly basis for a period of 10 weeks. After that, all necessary variables were recorded and data analyzed using SPSS version 16. Results: Most of the patients in our study were in the age group of 30-65 years. 26.9 % patients were in the range of 51-55 years old. 53.8% patients got no effect of intralesional injection of verapamil on pain while pain relieved in 38.5% of patients &amp; 7.7% patients experienced an increased in pain intensity after 10 weeks of intralesional injection of verapamil. 61.5%of patients satisfied with their sexual life after 10 week of injections &amp; 30.8% of patients remained unsatisfied with their sexual life while in 7.7%of patients symptoms aggravated. 53.8% of patients experienced no change in size of lesion and curvature of penis, while 30.8% got less than 50% reduction in size of lesion while 15.4% of patients got more than 50% reduction in size after 10 weeks. Practical implication: We can easily find the efficacy of Verapamil injection for management of Peyronie’s disease. Conclusion: This study concluded the efficacy of Verapamil injection for management of Peyronie’s disease disease causes significant decrease in size of lesion and improvement in sexual activity. Keywords: Peyronie’s disease, Improvement, Lesions, Significant

Hypofractionated Palliative Radiotherapy for Relapsed and Refractory High-Risk Neuroblastoma

<h3>Purpose/Objective(s)</h3> While palliative radiation therapy (RT) is frequently used in the management of relapsed/refractory high-risk neuroblastoma (HR-NBL) in pediatric patients, few studies have examined the role of palliative hypofractionated RT (hypo-RT) in HR-NBL. We sought to characterize outcomes after palliative-intent RT using conventionally fractionated (conv-RT) and hypo-RT regimens for patients with relapsed/refractory HR-NBL. <h3>Materials/Methods</h3> The Institutional Review Board approved a retrospective study of 37 patients who were diagnosed with HR-NBL between 1997-2021 and received palliative RT at two institutions. Patients receiving RT for central nervous system and liver metastases were excluded. Hypo-RT was defined as treatment courses using dose >2 Gy per fraction. Clinical and treatment characteristics and outcomes, including dates and locations of progression, were recorded. Fisher exact tests were used for categorical variables. Follow-up time was defined from start of RT. Cumulative incidence of in-field progression was analyzed using Gray's test with death as competing risk. Univariate analyses (UVA) were performed using Cox proportional-hazards regression. <h3>Results</h3> When analyzing by first course of palliative RT, there were 16 courses of conv-RT (43.2%) and 21 courses of hypo-RT (56.8%). The distribution of patients having further progression of disease before palliative RT, receiving palliative RT to bony and soft tissue sites, and undergoing chemotherapy before, during, and after palliative RT were not different between the two groups. With median follow-up of 10.3 months (range: 0.3-104.0), cumulative incidence of in-field progression at 10 months was not different between hypo-RT and conv-RT (30.0% vs 20.1%, p=0.80). After RT, patients had similar clinical benefit, defined as symptomatic relief or decrease in size of lesion (92.3% conv-RT vs. 90.0% hypo-RT, p=1.00). On UVA, further progression of disease before palliative RT, bony vs. soft tissue sites, receipt of chemotherapy before RT, receipt of concurrent chemotherapy with RT, and receipt of chemotherapy after RT were not associated with time to in-field progression. In addition, hypo-RT (Hazard ratio [HR]: 1.50, 95% confidence interval [CI]: 0.47-4.76, p=0.49) and biologically equivalent dose (BED) ≥29 Gy (HR: 1.44, 95% CI: 0.43-4.82, p=0.55) were not associated with time to in-field progression. <h3>Conclusion</h3> We found no difference in cumulative incidence of in-field progression and clinical outcomes between the conv-RT and hypo-RT groups. On UVA, hypo-RT and BED ≥29 Gy were not associated with longer time to in-field recurrence. Palliative hypo-RT can be considered for relapsed/refractory HR-NBL, especially when quality of life from shorter treatments may be of benefit.